Mother-to-child Transmission Research Articles

Nonhuman primate models of pediatric viral diseases

Infectious diseases are the leading cause of death in infants and children under 5 years of age. In utero exposure to viruses can lead to spontaneous abortion, preterm birth, congenital abnormalities or other developmental defects, often resulting in lifelong health sequalae. The underlying biological mechanisms are difficult to study in humans due to ethical concerns and limited sample access. Nonhuman primates (NHP) are closely related to humans, and pregnancy and immune ontogeny in infants are very similar to humans. Therefore, NHP are a highly relevant model for understanding fetal and postnatal virus-host interactions and to define immune mechanisms associated with increased morbidity and mortality in infants. We will discuss NHP models of viruses causing congenital infections, respiratory diseases in early life, and HIV. Cytomegalovirus (CMV) remains the most common cause of congenital defects worldwide. Measles is a vaccine-preventable disease, yet measles cases are resurging. Zika is an example of an emerging arbovirus with devastating consequences for the developing fetus and the surviving infant. Among the respiratory viruses, we will discuss influenza and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We will finish with HIV as an example of a lifelong infection without a cure or vaccine. The review will highlight (i) the impact of viral infections on fetal and infant immune development, (ii) how differences in infant and adult immune responses to infection alter disease outcome, and emphasize the invaluable contribution of pediatric NHP infection models to the design of effective treatment and prevention strategies, including vaccines, for human infants.

A prospective, multicenter study of hepatitis B birth-dose vaccine with or without hepatitis B immunoglobulin in preventing mother-to-child transmission of hepatitis B virus in Ethiopia

BackgroundHistorically, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) was considered uncommon in Africa, leading to a reluctant attitude to birth-dose HBV vaccination on the continent. As a randomized trial would be unethical, real-life data are needed to assess the effect of HBV birth-dose vaccine in Africa. MethodsA multicenter, prospective, observational study of hepatitis B surface antigen (HBsAg)-positive pregnant women and their infants was carried out in Ethiopia, from January 2019 to May 2021. Pregnant women were screened for HBsAg and HIV as part of routine antenatal care and/or delivery, and HBsAg-positive HIV-negative pregnant women were included in the study. HBV birth-dose vaccine and hepatitis B immunoglobulin (HBIg) were recommended but not all newborns received it as it was not national policy. All infants, however, received the pentavalent HBV vaccine at 6, 10, and 14 weeks of age. Vaccination status was confirmed from delivery ward charts and infant vaccination certificates. Infants were tested for HBsAg at 9 months of age and a positive result was taken as evidence of MTCT. FindingsOf 290 HBsAg-positive pregnant women, 168 mother/infant pairs returned for their 9-month follow-up visit and were included in this analysis. Two of 112 (1.8 %) infants who received birth-dose vaccine with HBIg, and 2 of 23 (8.7 %) who received birth-dose vaccine alone were HBsAg positive at nine months of age, compared to 8 of 33 (24.2 %) who received neither vaccine nor HBIg at birth (p = 0.002). High maternal viral load (>200,000 IU/ml; adjusted odds ratio [AOR] 10.4; 95 % confidence interval [CI] 1.2–92.1) and not receiving HBV birth-dose vaccine nor HBIg (AOR 29.2; 95 % CI 4.0–211.3) were independent predictors of MTCT. InterpretationBirth-dose HBV vaccine with or without HBIg significantly reduced the risk of MTCT of HBV in Ethiopia. Improved coverage of birth-dose HBV vaccine should be an urgent priority.

Congenital Cytomegalovirus Infection and Hearing Loss: It's Time to Screen.

Congenital CMV infection is the leading nongenetic cause of sensorineural hearing loss worldwide, yet most parents have never heard of it. The majority of infected newborns have no clinical signs of infection, although a substantial proportion may have hearing loss at birth or develop it later in life. As antiviral treatment with ganciclovir or valganciclovir initiated in the first month of age improves audiologic outcomes, there is an urgent need for timely identification of infected neonates. A targeted approach that tests neonates who refer on the newborn hearing screen has been implemented in many states and hospital programs, but it fails to identify about 40% of children who experience CMV-related hearing loss. A universal screening approach is optimal given the prevalence of congenital CMV infection, its associated sequelae, the availability of a simple saliva screening tool, the available antiviral treatment, and the directed therapies for hearing impairment.

Investigation of surfactant apoproteins and Brucella sp. antigens in the lungs of aborted bovine fetuses and neonatal calves delivered weak

The main objectives of this study were to investigate surfactant apoprotein expression (SP) and to detect Brucella sp. antigens in the lungs of aborted bovine fetuses and neonatal calves delivered weak. The Avidin-Biotin-Peroxidase Complex (ABC) and the indirect immunofluorescence (IF) techniques were applied, using antibodies to the lung surfactant apoproteins (SP-A, SP-B, SP-C) and Brucella sp. antigens. Hyperplasia of type II cells was also assessed by evaluating Thyroid Transcription Factor-1 (TTF-1), Proliferating Cell Nuclear Antigen (PCNA), and Cytokeratin Pan Type I/II (CK-P) markers. The study materials were the lungs of 46 aborted bovine fetuses and 20 neonatal calves delivered weak. Brucella sp.-positive fetal lungs displayed bronchopneumonia in 24 cases. The lungs of the weak-delivered neonates which were positive for Brucella sp. also showed pneumonia. Bacterial culture detected positivity in 11 of 46 fetuses and two neonates. IHC for Brucella sp. antigens found positivity in 22 of 46 fetuses and four neonates. Thus, our research revealed that the IHC technique using anti-Brucella sp. antibodies was useful for detecting Brucella sp. in autolytic and culture-negative fetuses. The study also found that surfactant synthesis begins close to the 7th month of gestation in bovine fetuses. Immunolabeling to SPs occurred in the cytoplasm of both type II and Clara cells, along with SP-C only in type II pneumocytes. The IF yielded dense labeling for Brucella sp. antigens, SP-B, and CK-P, respectively, in the phagocytic cells and epithelium of the airways. Also, pneumonia in newborn calves indicates an intrauterine infection by Brucella sp.

ADAR1 could be a potential diagnostic target for intrauterine infection patients

Intrauterine infection (IUI) is mainly an ascending infection in which vaginal and cervical pathogens ascend to the uterus and can affect the fetus. Until now, there is still no effective diagnostic biomarker for IUI, such as chorioamnionitis (CAM) and funisitis (FUN). Deoxyribonucleic acid (DNA)/Ribonucleic acid (RNA) editing molecules such as apolipoprotein-B mRNA-editing complex (APOBEC) 3 families and Adenosine deaminase family acting on RNA (ADAR)1 were examined in chorioamniotic membranes and umbilical cord of 83 patient samples. Furthermore, Ureaplasma parvum induced ADAR1 was investigated in human HTR-8/SVneo EVT cell line. ADAR1 had a significantly higher area under the curve (AUC) (0.721 and 0.745) than other APOBEC3s or cytokines in CAM and FUN patients. In vitro, ureaplasma parvum was demonstrated to activate ADAR1 (p = 0.025) and reduce RIG-I, IRF3, IFN-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:{\\upalpha\\:}$$\\end{document}, and IFN-β expression in EVT cell line (p = 0.005, p = 0.010, p < 0.001, and p = 0.018, respectively). High expression of ADAR1 was strongly associated with CAM and FUN patients (multivariate analyses; p = 0.035 and p = 0.002). ADAR1 could be a potential diagnostic target for IUI, such as CAM and FUN patients.

Profile of Perinatal Infections Among Abandoned Neonates Admitted in a Tertiary Hospital in Oman.

Little is known about the profile of perinatal infections among abandoned neonates, and there are no specific evidence-based guidelines on how to screen and manage these neonates. This study aimed to report the rate of perinatal infections among abandoned babies managed at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, over 15 years (2006-2021). This retrospective cohort study included all abandoned babies admitted at SQUH from January 2006 to December 2021. Demographic data, the area where they were found, anthropometric parameters, symptoms, investigations and management were included in the study. Of the 20 neonates included in this study, 11 (55%) were male and 9 (45%) were female; only 1 baby looked preterm. The estimated median age at admission was 1 day, while the median length of hospitalisation was 30 days. Infectious disease screening was not optimal for syphilis. Among the babies who were tested for perinatal infections such as HIV (n = 20), syphilis (n = 7), hepatitis B (n = 20) and hepatitis C (n = 19), none tested positive and all babies received the hepatitis B vaccine. Overall, 13 out of 20 babies received antibiotics for presumed sepsis. Zidovudine was given prophylactically to 3 neonates until the HIV test result was received. A total of 2 neonates were managed for gastroenteritis, 2 for sepsis and 1 for pneumonia; no death was recorded. A national protocol on what should be included in the screening and how to manage these babies is urgently needed to avoid adverse outcomes in this disadvantaged population.

Dysregulation of the mTOR-FMRP pathway and synapticplasticity in an environmental model of ASD.

Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8-10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined tothe intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

Congenital rubella syndrome and its protean manifestation in Nigeria

BackgroundCongenital rubella syndrome (CRS) arises from intrauterine infections with the rubella virus especially during the first trimester of pregnancy. It affects various systems resulting in disastrous outcomes.Case presentationWe present four cases of congenital rubella syndrome each manifesting a constellation of clinical features, some of which are cross-cutting with the aim of raising awareness among clinicians who may be involved in its management.ConclusionCongenital rubella syndrome is a deleterious condition with protean manifestations as demonstrated by the series presented in this report. The burden of CRS in developing countries still exists and can be curbed via immunization programme, introduction and strengthening of surveillance programme.

Cardiac Troponin-I Level at 24 hours of Age in Stable Newborn Infants Born at ≥35 Weeks of Gestation.

Cardiac troponin-I is a known biomarker of myocardial injury in adults and children but its diagnostic utility is unclear in newborns.This study aimed to establish normative data for troponin-I in stable newborns and assess any variation due to maternal diabetes status, mode of delivery, and Apgar scores. Prospective, observational study of stable newborn ≥35 weeks gestation admitted to a well-baby nursery at a single institution. Infants with respiratory distress, congenital infections, malformations, or syndromes were excluded. Troponin-I values were obtained by a validated point-of-care capillary blood sample at 24 hours of age. A total of 132 patients were included for analysis. Thirteen infants were born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy and analyzed as a subgroup, with the remaining 119 infants comprising the base cohort to establish baseline normative troponin-I levels in stable newborn infants. The mean (standard deviation) troponin-I level of infants in the base cohort group was 0.019 ± 0.018 ng/mL and in infants born with maternal SARS-CoV-2 infection during pregnancy troponin-I level was 0.081 ± 0.1 ng/mL (p < 0.001). In infants of the base cohort, there was no significant difference in troponin-I levels between diabetic versus nondiabetic mothers, vaginal birth versus cesarean section, and 5-minute Apgar score of <7 versus ≥7. Cardiac troponin-I level in healthy term newborns was 0.019 ± 0.018 ng/mL, which conforms to healthy children and adult lab values. There was no statistically significant difference in troponin-I levels in infants of maternal diabetes or normal glucose status, mode of delivery, cesarean versus vaginal, or 5-minute Apgar score of <7 or ≥7. Troponin-I levels in asymptomatic neonates born to mothers with a history of SARS-CoV-2 during pregnancy demonstrated an elevation when compared to the baseline group of infants. · Troponin-I level, biomarker of myocardial injury, in newborns not requiring delivery-room.. · Resuscitation is comparable to normal pediatric & adult population independent of mode of delivery or maternal diabetes status..

Fatal disseminated congenital cytomegalovirus infection in a twin preterm neonate: A clinical-pathological diagnosis

We report on a rare case of congenital cytomegalovirus (CMV) in a dichorionic diamniotic twins. The uniqueness of one of the twins having a fatal disseminated CMV infection with the other twin being normal has been discussed. In cases with no antenatal diagnosis, the role of post-clinical-pathological correlation using fetal autopsy has been described with fetal autopsy images (gross and microscopy). The possible immunological basis for the selective affection of one twin and a review of literature on similar cases have also been done.

A Review of Emerging Viral Pathogens and Current Concerns for Vertical Transmission of Infection.

Vertical transmission, or mother-to-child transmission, of bacterial, viral, or parasitic infection is rare due to the success of the barrier functions of the placental maternal-fetal interface, which provides physical, molecular, and immunological mechanisms to protect the developing fetus. Infections in pregnancy that can cross the placenta and reach the fetus can cause fetal loss, stillbirth, or prematurity or can lead to congenital infection, malformation of organs, and neonatal disease at birth. The acronym TORCH stands for Toxoplasma gondii, other, rubella, cytomegalovirus, and herpes simplex virus (HSV). Within the TORCH category of 'other,' there are increasing emerging viral pathogens that can pass from mother to fetus, including Ebola virus, Zika virus, and emerging arbovirus infections, including West Nile virus and Rift Valley fever virus. Although SARS-CoV-2 has rarely been reported to show transplacental spread, the recent COVID-19 pandemic has highlighted the importance of surveillance of new human pathogens with rapidly evolving transmission patterns. This article reviews the protective roles of the placental maternal-fetal interface, the concept of TORCH infections, and the emergence of viral pathogens currently causing concerns for vertical transmission from mother to fetus.

Immune responses drive chorioretinitis and retinal pathology after neonatal CMV infection.

Human cytomegalovirus (CMV) causes a common congenital infection leading to long-term neurological impairments including brain, cochlear, and ocular pathology. Infection of newborn mice with murine (M)CMV is an established model of neuropathology caused by congenital CMV infection, with recent work suggesting that brain pathology may be driven by immune responses. In the eye, however, CMV retinitis is thought to result from virus-driven necrosis in the absence of T cell responses. We found that MCMV infection of newborn mice recapitulates human eye disease after congenital CMV infection, including focal chorioretinitis, inflamed vasculature, and disrupted blood-retinal barriers. Moreover, infection drove extensive T cell infiltration of the retina and marked gliosis. Blocking immune responses generally, or via targeting the chemokine receptor CXCR3, did not exacerbate retinal disease but instead prevented pathology despite retinal MCMV infection. Thus, our data establish this model for studies of congenital retinal disease and show that the immune system drives pathology in the neonatal eye after MCMV infection.

Method for Identification and Bacterial Count Quantification in a Case of Ureaplasma Meningitis.

Intrauterine Ureaplasma infection is associated with chorioamnionitis and preterm birth. The difficulty of detecting Ureaplasma species by conventional culture methods makes definitive diagnosis of clinical infection challenging. Thus far, quantitative tests for Ureaplasma have been performed using adult cervical samples, amniotic fluid, and pediatric bronchial secretions, but quantification of bacterial count in central nervous system infections caused by Ureaplasma species has not been unreported. We report a case of culture-negative Ureaplasma meningitis in a preterm infant in whom novel techniques to identify this pathogen and quantify bacterial count were effective. We suspected meningitis based on a sustained reduction in cerebrospinal fluid (CSF) glucose levels. Multiple CSF cultures were sterile. We confirmed infection by Ureaplasma species using the melting temperature mapping method. Treatment with erythromycin and ciprofloxacin resulted in a gradual decrease in the bacterial count in the CSF to 0. Our study highlights the potential utility of the melting temperature mapping method as a new diagnostic tool for culture-negative Ureaplasma meningitis and establishes the utility of serial quantification of bacterial count to monitor response to therapy.

Diagnosis and treatment of infection specific to the perinatal period (Draft clinical recommendations for discussion by neonatologists and pediatricians)

Perinatal infections occupy a leading place among the causes of neonatal morbidity, maternal and perinatal mortality. Infections are among the main causes of termination of pregnancy and premature birth. The practical recommendations presented in the work are intended for doctors of obstetric institutions in order to make a clinical diagnosis of an infection specific to the perinatal period, the tactics of examination and treatment of newborn children. The clinical recommendations correspond to the latest scientific data on the topic, contain information that is applied to the practical activities of a neonatologist, intensive care specialist and pediatrician. These clinical recommendations contain information about infections specific to the perinatal period, including the definition, frequency of occurrence, etiology of infections, pathogenetic mechanisms of disease development Numerous high-risk factors for infection of the fetus and newborn are described in detail. The document discusses and proposes the classification of the disease, the criteria for the adoption of the diagnosis. The features of the clinical picture of the disease are described, it is noted that the inflammatory process in a newborn child can be localized in any organ or acquire a systemic (generalized) character, in some cases, the ingress of an infectious agent into a macroorganism is not necessarily accompanied by clinical manifestations, which indicates an asymptomatic or subclinical course of infection. The recommendations provide advanced laboratory and instrumental diagnostics. The stages of treatment are described, including the choice and correction of antibacterial therapy, taking into account the peculiarities of the mother’s anamnesis, the child’s gestation period and the etiology of the disease. These clinical recommendations have been prepared taking into account the level of credibility of the recommendations and the level of reliability of the evidence.These practical recommendations are offered for public discussion and are posted in full on the website of the Ministry of Health of the Russian Federation.

Auditory and Vestibular Involvement in Congenital Cytomegalovirus Infection.

Congenital cytomegalovirus infection (cCMV) is a frequent cause of non-hereditary sensorineural hearing loss (SNHL) and developmental disabilities. The contribution of cCMV to childhood hearing loss has been estimated to be about 25% of all hearing loss in children at 4 years of age. Although the vestibular insufficiency (VI) in cCMV has not been well-characterized and therefore, underestimated, recent studies suggest that VI is also frequent in children with cCMV and can lead to adverse neurodevelopmental outcomes. The pathogenesis of SNHL and VI in children with cCMV has been thought to be from direct viral cytopathic effects as well as local inflammatory responses playing a role. Hearing loss in cCMV can be of varying degrees of severity, unilateral or bilateral, present at birth or develop later (late-onset), and can progress or fluctuate in early childhood. Therefore, newborn hearing screening fails to identify a significant number of children with CMV-related SNHL. Although the natural history of cCMV-associated VI has not been well characterized, recent data suggests that it is likely that VI also varies considerably with respect to the laterality, timing of onset, degree of the deficit, and continued deterioration during early childhood. This article summarizes the current understanding of the natural history and pathogenesis of auditory and vestibular disorders in children with cCMV.

Surgery and the first 8000 days of life: a review

Abstract The first 8000 days of life, from birth to adulthood, encompasses critical phases that shape a child's health and development. While global health efforts have focused on the first 1000 days, the next 7000 days (ages 2–21) are equally vital, especially concerning the unmet burden of surgical conditions in low- and middle-income countries (LMICs). Approximately 1.7 billion children globally lack access to essential surgical care, with LMICs accounting for 85% of these unmet needs. Common surgical conditions, including congenital anomalies, injuries, infections, and pediatric cancers, often go untreated, contributing to significant mortality and disability. Despite the substantial need, LMICs face severe workforce and infrastructure shortages, with most pediatric surgical conditions requiring specialized skills, equipment, and tailored healthcare systems. Economic analyses have shown that pediatric surgical interventions are cost-effective, with substantial societal benefits. Expanding surgical care for children in LMICs demands investments in workforce training, infrastructure, and health systems integration, complemented by innovative funding and equitable global partnerships. Prioritizing surgical care within national health policies and scaling up children's surgery through initiatives like the Optimal Resources for Children's Surgical Care can improve health outcomes, align with Sustainable Development Goals, and foster equity in global health. Addressing the surgical care gap in LMICs will reduce preventable mortality, enhance quality of life, and drive sustainable growth, emphasizing surgery as an essential component of universal health coverage for children.

Defining Appropriate Comparator Populations for Placental Pathology for Pregnant People With HIV.

Background. Widespread adoption of antiretroviral therapy has reduced perinatal transmission of HIV; however, people living with HIV (PWH) have higher rates of preterm birth and hypertensive disorders of pregnancy. The placenta is the critical fetal support organ in pregnancy, and multiple investigations have sought associations in PWH between HIV and placental pathology. However, results have been inconclusive. We posit that selection of control group populations influences the apparent anomalies in placentas from PWH and examined the differences seen between these placentas and those of four comparator populations. Methods. Placentas from PWH were compared with those from all patients without HIV, controls from a recent study of severe acute respiratory syndrome coronavirus 2 in pregnancy, patients with a history of melanoma-an indication for examination relatively orthogonal to other problems in pregnancy, and patients paired with PWH using propensity score matching. Results. People living with HIV differ in demographics and comorbidities from comparator groups other than propensity score-matched patients. Placentas from PWH had higher rates of acute placental inflammation, including maternal inflammatory response and fetal inflammatory response, than multiple comparator groups. Placentas from PHW had lower rates of chronic placental inflammation than three of four comparator groups, including the largest comparator group and the group matched to PWH using propensity scores. Conclusion. Differences in placental pathology in PWH depend on the comparator group. Commonly used comparator groups have significantly different demographic and comorbidity profiles, suggesting they are inappropriate comparators for PWH. Propensity score matching may be useful in identifying comparator populations.

Epilepsy genetics in the paediatric population of the Eastern Anatolia region of Turkey

This study investigates the genetic causes of epilepsy in 166 paediatric patients under the age of 16 from the East Anatolian region of Turkey, who were treated at Erzurum City Hospital between 2018 and 2023. Patients with early-onset seizures, a family history of epilepsy or intellectual disability was selected for genetic analysis using a next-generation sequencing (NGS) gene panel targeting 449 genes associated with epilepsy and epileptic encephalopathy. The analysis revealed that pathogenic or probable pathogenic mutations were present in 14.8% (32 patients), highlighting the significant role of genetic factors in the aetiology of epilepsy in this population. In addition, 30.6% (66 patients) carried variants of uncertain significance (VUS), which, although not classified as pathogenic, have potential clinical relevance. Many epilepsy-related genes follow an autosomal dominant inheritance pattern, meaning that VUSs may gain pathogenic significance as more data and global studies accumulate, emphasising the evolving nature of genetic research. In addition to genetic factors, other aetiological causes such as perinatal insults (15.3%) and infections (7.9%) were identified, highlighting the multifactorial origin of epilepsy. While pathogenic mutations currently serve as important diagnostic and therapeutic markers, the role of VUS should not be underestimated. Genetic testing has proven to be essential for understanding the complex causes of epilepsy, providing opportunities for personalised treatment and genetic counselling. This study highlights the importance of genetic testing in regions such as Eastern Anatolia, where both environmental and genetic factors may influence the prevalence of epilepsy. As genetic databases expand, it is likely that the understanding of VUS will evolve, improving the clinical management of epilepsy through more targeted therapies and improved outcomes.

Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring

BackgroundCongenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection.MethodsCMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1.ResultsIncreased PGE2 levels and increased proportions of Cox-1+ and Cox-2+ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1+ fetal, but not neonatal, microglia, while leaving the proportions of Cox-2+ microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups.ConclusionOverall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.

Tenofovir and Hepatitis B Virus Transmission During Pregnancy

Standard care for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in highly viremic mothers consists of maternal antiviral prophylaxis beginning at gestational week 28 combined with an HBV vaccine series and HBV immune globulin (HBIG) at birth. However, HBIG is unavailable in some resource-limited areas. To determine whether initiating tenofovir disoproxil fumarate (TDF) at gestational week 16 combined with HBV vaccinations for infants is noninferior to the standard care of TDF at gestational week 28 combined with HBV vaccinations and HBIG for infants in preventing MTCT in mothers with HBV and high levels of viremia. An unblinded, 2-group, randomized, noninferiority clinical trial was conducted in 7 tertiary care hospitals in China. A total of 280 pregnant individuals (who all identified as women) with HBV DNA levels greater than 200 000 IU/mL were enrolled between June 4, 2018, and February 8, 2021. The final follow-up occurred on March 1, 2022. Pregnant individuals were randomly assigned to receive either TDF starting at gestational week 16 with HBV vaccinations for the infant or TDF starting at gestational week 28 with HBV vaccinations and HBIG administered to the infant. The primary outcome was the MTCT rate, defined as detectable HBV DNA greater than 20 IU/mL or hepatitis B surface antigen positivity in infants at age 28 weeks. Noninferiority was established if the MTCT rate in the experimental group did not increase by more than an absolute difference of 3% compared with the standard care group, as measured by the upper limit of the 2-sided 90% CI. Among 280 pregnant individuals who enrolled in the trial (mean age, 28 years; mean gestational age at enrollment, 16 weeks), 265 (95%) completed the study. Among all live-born infants, using the last observation carried forward, the MTCT rate was 0.76% (1/131) in the experimental group and 0% (0/142) in the standard care group. In the per-protocol analysis, the MTCT rate was 0% (0/124) in the experimental group and 0% (0/141) in the standard care group. The between-group difference was 0.76% (upper limit of the 2-sided 90% CI, 1.74%) in all live-born infants and 0% (upper limit of the 2-sided 90% CI, 1.43%) in the per-protocol analysis. Both comparisons met the criterion for noninferiority. Rates of congenital defects and malformations were 2.3% (3/131) in the experimental group and 6.3% (9/142) in the standard care group (difference, 4% [2-sided 95% CI, -8.8% to 0.7%]). Among pregnant women with HBV and high levels of viremia, TDF beginning at gestational week 16 combined with HBV vaccination for infants was noninferior to the standard care of TDF beginning at gestational week 28 combined with HBIG and HBV vaccination for infants. These results support beginning TDF at gestational week 16 combined with infant HBV vaccine to prevent MTCT of HBV in geographic areas where HBIG is not available. ClinicalTrials.gov Identifier: NCT03476083.